Molecular Cancer Research最新文献

{"title":"METTL14-mediated Bim mRNA m6A modification augments osimertinib sensitivity in EGFR-mutant NSCLC cells.","authors":"Siwen Fan, Xinwu Lv, Chuantao Zhang, Bingbing Zeng, Yanqing Liang, Danyang Chen, Zumin Xu, Pan Li, Shanshan Wu, Hao Liu, Kai Luo, Zongcai Liu, Yanmei Yi","doi":"10.1158/1541-7786.MCR-23-1018","DOIUrl":"https://doi.org/10.1158/1541-7786.MCR-23-1018","url":null,"abstract":"<p><p>Resistance to osimertinib represents a significant challenge for the successful treatment of non-small cell lung cancer (NSCLC) harboring activating mutations in epidermal growth factor receptor (EGFR). N6-methyladenosine (m6A) on mRNAs is critical for various biological processes, yet whether m6A regulates osimertinib resistance of NSCLC remains unknown. In this study, we demonstrated that developing osimertinib-resistant phenotypes depends on m6A reduction resulting from downexpression of m6A methyltransferase METTL14 in EGFR-mutant NSCLCs. Both in vitro and in vivo assay showed that specific knockdown of METTL14 was sufficient to confer osimertinib resistance and elevated expression of METTL14 rescued the efficacy of osimertinib in the resistant NSCLC cells. Mechanistically, METTL14 promoted m6A methylation of pro-apoptotic Bim mRNA and increased Bim mRNA stability and expression, resulting in activating the Bim-dependent pro-apoptotic signaling and thereby promoting osimertinib-induced cell apoptosis. Analysis of clinical samples revealed that decreased expression of METTL14 was observed in osimertinib-resistant NSCLC tissues and significantly associated with a poor prognosis. In conclusion, our study reveals a novel regulatory mechanism by which METTL14-mediated m6A methylation of Bim mRNA inhibited osimertinib resistance of NSCLC cells. It offers more evidences for the involvement of m6A modification in regulation of osimertinib resistance, and provides potential therapeutic targets for novel approaches to overcome the tolerance of osimertinib and other EGFR-TKIs. Implications: This study offers more evidences for the involvement of METTL14-mediated m6A modification in regulation of osimertinib resistance, and provides potential therapeutic targets for novel approaches to overcome the tolerance of osimertinib and other EGFR-TKIs.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141492786","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Vasorin Exocytosed from Glioma Cells Facilitates Angiogenesis via VEGFR2/AKT Signaling Pathway.","authors":"Ying Zhong, Hui Kang, Ziqing Ma, Jiayu Li, Zixi Qin, Zixuan Zhang, Peiwen Li, Ying Zhong, Lihui Wang","doi":"10.1158/1541-7786.MCR-23-0469","DOIUrl":"10.1158/1541-7786.MCR-23-0469","url":null,"abstract":"<p><p>Glioma is a highly vascularized tumor of the central nervous system. Angiogenesis plays a predominant role in glioma progression and is considered an important therapeutic target. Our previous study showed that vasorin (VASN), a transmembrane protein, is overexpressed in glioma and promotes angiogenesis; however, the potential mechanism remains unclear. In this study, we found that human vascular endothelial cells (hEC) co-cultured with VASN-overexpressing glioma cells exhibited accelerated migration ability and increased expression of VASN originated from glioma cells. VASN was found in exosomes secreted by glioma cells and could be taken up by hECs. hECs showed more edge filopodia and significantly upregulated expression of endothelial tip cell marker gene and protein levels after co-culture with VASN-overexpressing glioma cells. In clinical glioma tissue and orthotopic transplantation glioma tissue, the vascular density and the number of vascular endothelial cells with a tip cell phenotype in VASN-overexpressed tissues were significantly higher than in tissues with low expression. At the molecular level, VASN interacted with VEGFR2 and caused internalization and autophosphorylation of VEGFR2 protein, and then activated the AKT signaling pathway. Our study collectively reveals the function and mechanism of VASN in facilitating angiogenesis in glioma, providing a new therapeutic target for glioma.</p><p><strong>Implications: </strong>These findings demonstrate that VASN exocytosed from glioma cells enhanced the migration of vascular endothelial cells by VEGFR2/AKT signaling pathway.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140132100","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"NAP1L1 Promotes Endometrial Cancer Progression via EP300-Mediated DDX5 Promoter Acetylation.","authors":"Xiangfei Zhu, Yishan Li, Zhiying Shao, Xiaoyuan Lu, Youguo Chen","doi":"10.1158/1541-7786.MCR-23-0871","DOIUrl":"https://doi.org/10.1158/1541-7786.MCR-23-0871","url":null,"abstract":"<p><p>Endometrial cancer (EC) is one of the predominant tumors of the female reproductive system. In this current study, we investigated the functions and related mechanisms of NAP1L1/DDX5 in EC. This retrospective study analyzed the medical records of EC patients, collected tissue samples for NAP1L1 and DDX5 staining, and conducted survival analysis using the Kaplan-Meier method. To evaluate the impact of NAP1L1 and/or DDX5 on cellular processes in EC cells, several techniques were employed. These included CCK-8 assay, wound healing assay, Transwell assay, as well as overexpression or knockdown of target gene expression. Additionally, ChIP, dual luciferase reporter gene, Co-IP assay were utilized to confirm the interaction between NAP1L1, EP300 and DDX5. Furthermore, qRT-PCR, western blot and Co-IP assay were performed to analyze the modulation of NAP1L1/DDX5 in Wnt/β-catenin. NAP1L1 and DDX5 expression were upregulated in EC tissues, and correlated with poor prognosis. NAP1L1/DDX5 promoted EC cell proliferation, migration and invasion. NAP1L1 promotes acetylation and transcription by recruiting EP300 to the DDX5 promoter. DDX5 could activate Wnt/β-catenin signal by binding to β-catenin. In animal models, knockdown of NAP1L1 inhibits EC tumor growth and lung metastasis. To sum up, our study demonstrated that NAP1L1 promoted the malignant phenotypes of EC cells via recruiting EP300 to promote DDX5 acetylation, thus activating the Wnt/β-catenin signaling pathway. Implications: Our research findings indicate that targeting the NAP1L1/EP300/DX5 axis might be a new potential treatment option for endometrial cancer.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141492801","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"lncRNA-WAL promotes triple-negative breast cancer aggression by inducing β-catenin nuclear translocation.","authors":"Hongyan Huang, Haiyun Jin, Rong Lei, Zhanghai He, Shishi He, Jiewen Chen, Phei Er Saw, Zhu Qiu, Guosheng Ren, Yan Nie","doi":"10.1158/1541-7786.MCR-23-0334","DOIUrl":"https://doi.org/10.1158/1541-7786.MCR-23-0334","url":null,"abstract":"<p><p>Because of its insensitivity to existing radiotherapy, namely chemotherapy and targeted treatments, triple-negative breast cancer (TNBC) remains a great challenge to overcome. Increasing evidence has indicated abnormal Wnt/β-catenin pathway activation in TNBC but not luminal or HER2+ breast cancer, and lncRNAs play a key role in a variety of cancers. Through lncRNA microarray profiling between activated and inactivated wnt/β-catenin pathway of TNBC tissues, lnc-WAL (wnt/β-catenin associated lncRNA; WAL) was selected as the top upregulated lncRNA in wnt/β-catenin pathway activation compared with the inactivation group. RIP-seq was used to compare the β-catenin and IgG groups, where lnc-WAL could interact with β-catenin. Clinically, increased lnc-WAL in TNBC tumor tissue was associated with shorter survival. lnc-WAL promoted EMT, the proliferation, migration and invasion of breast cancer stem cells (BCSCs), and TNBC cells. Mechanistically, lnc-WAL inhibited β-catenin protein degradation via Axin-mediated phosphorylation at serine 45. Subsequently, β-catenin accumulated in the nucleus and activated the target genes. Importantly, wnt/β-catenin pathway activation stimulated the transcription of lnc-WAL. These results pointed to a master regulatory role of lnc-WAL/Axin/β-catenin in the malignant progression of TNBC. Our findings provide important clinical translational evidence that lnc-WAL may be a potential therapeutic target against TNBC. Implications: The positive feedback between lnc-WAL and the Wnt/β-catenin pathway promotes TNBC progression, and lnc-WAL could be a potential prognostic marker for TNBC patients.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141469682","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Serotonin Receptor HTR2B Facilitates Colorectal Cancer Metastasis via CREB1-ZEB1 Axis-Mediated Epithelial-Mesenchymal Transition.","authors":"Tao Li, Lei Wei, Xin Zhang, Bin Fu, Yunjiang Zhou, Mengdi Yang, Mengran Cao, Yaxin Chen, Yingying Tan, Yongwei Shi, Leyin Wu, Chenyuan Xuan, Qianming Du, Rong Hu","doi":"10.1158/1541-7786.MCR-23-0513","DOIUrl":"10.1158/1541-7786.MCR-23-0513","url":null,"abstract":"<p><p>A number of neurotransmitters have been detected in tumor microenvironment and proved to modulate cancer oncogenesis and progression. We previously found that biosynthesis and secretion of neurotransmitter 5-hydroxytryptamine (5-HT) was elevated in colorectal cancer cells. In this study, we discovered that the HTR2B receptor of 5-HT was highly expressed in colorectal cancer tumor tissues, which was further identified as a strong risk factor for colorectal cancer prognostic outcomes. Both pharmacological blocking and genetic knocking down HTR2B impaired migration of colorectal cancer cell, as well as the epithelial-mesenchymal transition (EMT) process. Mechanistically, HTR2B signaling induced ribosomal protein S6 kinase B1 (S6K1) activation via the Akt/mTOR pathway, which triggered cAMP-responsive element-binding protein 1 (CREB1) phosphorylation (Ser 133) and translocation into the nucleus, then the phosphorylated CREB1 acts as an activator for ZEB1 transcription after binding to CREB1 half-site (GTCA) at ZEB1 promoter. As a key regulator of EMT, ZEB1, therefore, enhances migration and EMT process in colorectal cancer cells. We also found that HTR2B-specific antagonist (RS127445) treatment significantly ameliorated metastasis and reversed EMT process in both HCT116 cell tail-vein-injected pulmonary metastasis and CT26 cell intrasplenic-injected hepatic metastasis mouse models.</p><p><strong>Implications: </strong>These findings uncover a novel regulatory role of HTR2B signaling on colorectal cancer metastasis, which provide experimental evidences for potential HTR2B-targeted anti-colorectal cancer metastasis therapy.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139913149","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"lncRNA JPX Promotes Tumor Progression by Interacting with and Destabilizing YTHDF2 in Cutaneous Melanoma.","authors":"Dan Luo, Hui Tang, Liuchang Tan, Long Zhang, Lei Wang, Qionghui Cheng, Xia Lei, Jinjin Wu","doi":"10.1158/1541-7786.MCR-23-0701","DOIUrl":"10.1158/1541-7786.MCR-23-0701","url":null,"abstract":"<p><p>Aberrant long noncoding RNAs just proximal to Xist (lncRNA JPX) expression levels have been detected in multiple tumors. However, whether JPX is involved in melanoma progression remains unclear. Our study showed that JPX expression is significantly increased in melanoma tissues and cell lines. To clarify the effect of JPX on cutaneous melanoma, we successfully generated JPX-overexpressing or JPX-knockdown A375 and A2058 cells. CCK-8, colony formation EdU, Transwell, and cell-cycle phase assays were performed, and subcutaneously implanted tumor models were used to determine the function of JPX in cutaneous melanoma. The results showed that JPX knockdown reduced the proliferation and migration of malignant melanoma cells both in vitro and in vivo. To further elucidate the molecular mechanism of JPX-induced cutaneous melanoma deterioration, we performed RNA pull-down, RNA immunoprecipitation, coimmunoprecipitation, Western blot, and RNA-sequence analyses. JPX can directly interact with YTHDF2 and impede the protection of YTHDF2 from ubiquitin-specific protease 10 (USP10), which promotes its deubiquitination. Thus, JPX decreases protein stability and promotes the degradation of YTHDF2, thereby stabilizing BMP2 mRNA and activating AKT phosphorylation. Overall, our study revealed a novel effect of JPX on YTHDF2 ubiquitination, suggesting the possibility of blocking the JPX/USP10/YTHDF2/BMP2 axis as a prospective therapeutic approach for cutaneous melanoma.</p><p><strong>Implications: </strong>This study highlights the ubiquitination effect of USP10 and JPX on YTHDF2 in cutaneous melanoma, and proposes that the JPX/USP10/YTHDF2/BMP2 axis may be a prospective therapeutic target for cutaneous melanoma.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140028513","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Systematic Characterization of p53-Regulated Long Noncoding RNAs across Human Cancers Reveals Remarkable Heterogeneity among Different Tumor Types.","authors":"Kausik Regunath, Vitalay Fomin, Zhaoqi Liu, Pingzhang Wang, Mainul Hoque, Bin Tian, Raul Rabadan, Carol Prives","doi":"10.1158/1541-7786.MCR-23-0295","DOIUrl":"10.1158/1541-7786.MCR-23-0295","url":null,"abstract":"<p><p>The p53 tumor suppressor protein, a sequence-specific DNA binding transcription factor, regulates the expression of a large number of genes, in response to various forms of cellular stress. Although the protein coding target genes of p53 have been well studied, less is known about its role in regulating long noncoding genes and their functional relevance to cancer. Here we report the genome-wide identification of a large set (>1,000) of long noncoding RNAs (lncRNA), which are putative p53 targets in a colon cancer cell line and in human patient datasets from five different common types of cancer. These lncRNAs have not been annotated by other studies of normal unstressed systems. In the colon cancer cell line, a high proportion of these lncRNAs are uniquely induced by different chemotherapeutic agents that activate p53, whereas others are induced by more than one agent tested. Further, subsets of these lncRNAs independently predict overall and disease-free survival of patients across the five different common cancer types. Interestingly, both genetic alterations and patient survival associated with different lncRNAs are unique to each cancer tested, indicating extraordinary tissue-specific variability in the p53 noncoding response. The newly identified noncoding p53 target genes have allowed us to construct a classifier for tumor diagnosis and prognosis.</p><p><strong>Implications: </strong>Our results not only identify myriad p53-regulated long noncoding (lncRNA), they also reveal marked drug-induced, as well as tissue- and tumor-specific heterogeneity in these putative p53 targets and our findings have enabled the construction of robust classifiers for diagnosis and prognosis.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139932211","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"FATP5 Is Indispensable for the Growth of Intrahepatic Cholangiocarcinoma.","authors":"Diyala Shihadih, Xue Wang, Peter-James H Zushin, Pavlo Khodakivskyi, Hyo Min Park, Emily Tso, Jena Shiblak, Angela Misic, Sharon M Louie, Catherine Ward, Marc Hellerstein, Daniel K Nomura, Elena Goun, Francesco Urigo, Diego F Calvisi, Xin Chen, Andreas Stahl","doi":"10.1158/1541-7786.MCR-23-0389","DOIUrl":"10.1158/1541-7786.MCR-23-0389","url":null,"abstract":"<p><p>Altered lipid metabolism is a common hallmark of various cancers, including intrahepatic cholangiocarcinoma (ICC), a highly lethal carcinoma that lacks effective treatment options. To elucidate the lipid metabolism changes in ICC, we coupled the expression of the firefly luciferase gene (FFL) to AKT1 (AKT-FFL) via an IRES linker, and then hydrodynamically injected mice with AKT-FFL and Notch1 intracellular cytoplasmic domain (NICD) to establish a luciferase-positive ICC model. This model not only enabled us to monitor and quantify tumor growth by injecting the mice with luciferin, but also allowed us to assess the fatty acid uptake rate by injecting the mice with free fatty acid luciferin (FFA-Luc). The ICC model exhibited robust uptake of exogenous fatty acids compared with the HCC model induced by AKT-FFL/ neuroblastoma Ras (Ras). Lipidomics analysis showed a dramatically higher level of fatty acid in ICC, further supporting the increased fatty acids uptake. Mechanistic studies identified FATP5 as the predominant mediator of fatty acid uptake required for ICC growth using Fatp5 knockout mice and AAV-based shRNA silencing of Fatp5. Our study discovered a novel therapeutic target for the treatment of ICC and shed light on the contributions of lipid metabolism to ICC development.</p><p><strong>Implications: </strong>This study provides the first in vivo evidence that FATP5 is a potential therapeutic target for treating ICC.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139735729","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PIGA Mutations and Glycosylphosphatidylinositol Anchor Dysregulation in Polyposis-Associated Duodenal Tumorigenesis.","authors":"Elena Meuser, Kyle Chang, Angharad Walters, Joanna J Hurley, Hannah D West, Iain Perry, Matthew Mort, Laura Reyes-Uribe, Rebekah Truscott, Nicholas Jones, Rachel Lawrence, Gareth Jenkins, Peter Giles, Sunil Dolwani, Bilal Al-Sarireh, Neil Hawkes, Emma Short, Geraint T Williams, Melissa W Taggart, Kim Luetchford, Patrick M Lynch, Diantha Terlouw, Maartje Nielsen, Sarah-Jane Walton, Andrew Latchford, Susan K Clark, Julian R Sampson, Eduardo Vilar, Laura E Thomas","doi":"10.1158/1541-7786.MCR-23-0810","DOIUrl":"10.1158/1541-7786.MCR-23-0810","url":null,"abstract":"<p><p>The pathogenesis of duodenal tumors in the inherited tumor syndromes familial adenomatous polyposis (FAP) and MUTYH-associated polyposis (MAP) is poorly understood. This study aimed to identify genes that are significantly mutated in these tumors and to explore the effects of these mutations. Whole exome and whole transcriptome sequencing identified recurrent somatic coding variants of phosphatidylinositol N-acetylglucosaminyltransferase subunit A (PIGA) in 19/70 (27%) FAP and MAP duodenal adenomas, and further confirmed the established driver roles for APC and KRAS. PIGA catalyzes the first step in glycosylphosphatidylinositol (GPI) anchor biosynthesis. Flow cytometry of PIGA-mutant adenoma-derived and CRISPR-edited duodenal organoids confirmed loss of GPI anchors in duodenal epithelial cells and transcriptional profiling of duodenal adenomas revealed transcriptional signatures associated with loss of PIGA.</p><p><strong>Implications: </strong>PIGA somatic mutation in duodenal tumors from patients with FAP and MAP and loss of membrane GPI-anchors may present new opportunities for understanding and intervention in duodenal tumorigenesis.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11148540/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140306246","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Surgical Tumor Resection Deregulates Hallmarks of Cancer in Resected Tissue and the Surrounding Microenvironment.","authors":"Rohan Chaubal, Nilesh Gardi, Shalaka Joshi, Gouri Pantvaidya, Rasika Kadam, Vaibhav Vanmali, Rohini Hawaldar, Elizabeth Talker, Jaya Chitra, Poonam Gera, Dimple Bhatia, Prajakta Kalkar, Mamta Gurav, Omshree Shetty, Sangeeta Desai, Neeraja M Krishnan, Nita Nair, Vani Parmar, Amit Dutt, Binay Panda, Sudeep Gupta, Rajendra Badwe","doi":"10.1158/1541-7786.MCR-23-0265","DOIUrl":"10.1158/1541-7786.MCR-23-0265","url":null,"abstract":"<p><p>Surgery exposes tumor tissue to severe hypoxia and mechanical stress leading to rapid gene expression changes in the tumor and its microenvironment, which remain poorly characterized. We biopsied tumor and adjacent normal tissues from patients with breast (n = 81) and head/neck squamous cancers (HNSC; n = 10) at the beginning (A), during (B), and end of surgery (C). Tumor/normal RNA from 46/81 patients with breast cancer was subjected to mRNA-Seq using Illumina short-read technology, and from nine patients with HNSC to whole-transcriptome microarray with Illumina BeadArray. Pathways and genes involved in 7 of 10 known cancer hallmarks, namely, tumor-promoting inflammation (TNF-A, NFK-B, IL18 pathways), activation of invasion and migration (various extracellular matrix-related pathways, cell migration), sustained proliferative signaling (K-Ras Signaling), evasion of growth suppressors (P53 signaling, regulation of cell death), deregulating cellular energetics (response to lipid, secreted factors, and adipogenesis), inducing angiogenesis (hypoxia signaling, myogenesis), and avoiding immune destruction (CTLA4 and PDL1) were significantly deregulated during surgical resection (time points A vs. B vs. C). These findings were validated using NanoString assays in independent pre/intra/post-operative breast cancer samples from 48 patients. In a comparison of gene expression data from biopsy (analogous to time point A) with surgical resection samples (analogous to time point C) from The Cancer Genome Atlas study, the top deregulated genes were the same as identified in our analysis, in five of the seven studied cancer types. This study suggests that surgical extirpation deregulates the hallmarks of cancer in primary tumors and adjacent normal tissue across different cancers.</p><p><strong>Implications: </strong>Surgery deregulates hallmarks of cancer in human tissue.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11148542/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139940334","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}